The majority of non-Hodgkin's lymphomas (NHL) are malignancies of CD2O+ B-lymphocytes. There are approximately 55,000 new cases of NHL each year; and for unexplained reasons, the incidence is rising. A new form of treatment for B-cell NHL involves the use of rituximab, a monoclonal antibody that is targeted to the CD2O antigen. Yttrium-90 is a radioisotope that can be linked to the anti-CD2O antibody to target radiation to the malignant B-cells. Preliminary studies have established a safe single dose of Yttrium-90 anti-CD2O antibody (Y2B8) which will produce a tumor response in 82 percent of patients (pts) with low-grade or follicular NHL. The primary toxicity of Y2B8 is reversible myelosuppression, which results in neutropenia and thrombocytopenia and the concomitant increased risk for infection or bleeding. Indium-111 conjugated to the anti-CD2O antibody (In2B8) has been developed to predict tumor and normal organ dosimetry. It is hypothesized that retreatment with Y2B8 delivered 3-4 months after the first dose will improve the complete remission (CR) rate as well as the duration of response. The overall objective of this proposal is to develop a safe treatment strategy that utilizes two sequential doses of Y2B8 separated by 12-16 weeks. After the maximum tolerated two doses (MTD) of Y2B8 is established, a phase II trial will be done to learn if the CR rate can be doubled to 50 percent. It is important to learn the normal organ (including bone marrow) and tumor dosimetry using In2B8 scanning prior to each dose of Y2B8. Statistical models using the In2B8 dosimetry results and marrow mass calculations from Tc radiocolloid scans will be investigated to learn whether marrow toxicity can be predicted. The results of the In2B8 scans will be correlated with computerized tomography (CT) and positron emission tomography (PET) scans. CT and PET will be important to evaluate at the time of the second dose of Y2B8 because many pts have residual masses detected by CT. It is hypothesized that if the residual masses are positive by In2B8 or PET scanning that this will represent residual lymphoma rather than benign scar tissue. Since myelosuppression is the major toxicity of Y2B8, it is hypothesized that this can be decreased by utilizing prophylactic colony stimulating factors. After the MTD is established, additional pts will be treated with prophylactic granulocyte macrophage colony stimulating factor (GM-CSF) and thrombopoietic growth factor (Interleukin-II, oprelvekin) to learn whether the myelosuppression can be ameliorated and whether the dose of Y2B8 can be increased. Bone marrow exams will be performed before and after Y2B8 to evaluate marrow toxicity and effect on marrow cytogenetics. Although it is unusual for humans to develop an antibody to this antibody (human anti-murine anti-mouse antibody - HAMA), it is unknown whether pts will have a higher HAMA rate after two doses of Y2B8 and this will be examined in this protocol. We anticipate that this novel radioimmunotherapy approach will result in more effective treatment for pts with NHL.